4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid salt crystal forms

Abstract

The present invention relates to toluenesulfonic acid addition salt crystals of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3 -de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone, and methods of using such crystals as 5-hydroxytryptamine 2 receptor agonists and antagonists in treating disorders of the central nervous system.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

This application use used herein, the term “crystal” or “crystals” or “crystalline” or “crystalinic” refers to any solid that has a short or long range order of the molecules, atoms or ions in a fixed lattice arrangement. Salt Crystals of the Present Invention may be in a single crystal form. Therefore, the Salt Crystals of the Present Invention may be in a triclinic, monoclinic, orthorhombic, tetragonal, rhobohedral rhombohedral, hexagonal or cubic crystal form or mixtures thereof. In particular, the Salt Crystals of the Present Invention are in dry crystalline form. In another embodiment, the Salt Crystals of the Present Invention are in needle form. In still another embodiment, the Salt Crystals of the Present Invention are in thin flak flake or flake fragment form. In a particular embodiment, the Salt Crystals of the Present Invention are substantially free of other forms, e.g., free of amorphous or other crystal forms.

The term “substantially free” of other crystal forms refer to less than about 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1%, most preferably less than about 0.01 wt. % of other crystal forms, e.g., amorphous or other crystal forms. For example, the Salt Crystals of the Present Invention is in Form A and are free or substantially free of other salt forms, e.g., greater than 90 wt. % of Form A with less than 10 wt. % of the amorphous or other crystal forms. In another example, the Salt Crystals of the Present Invention is in Form B free or substantially free of other salt forms, e.g., greater than 90 wt. % of Form B with less than 10 wt. % of the amorphous or other crystal forms. Preferably, the Salt Crystals of the Present Invention comprises greater than 99 wt. % a single crystal form. Similar to “substantially free”

The term “predominantly” or “substantially entirely in a single form” refers to less than about 10 wt. %, preferably less than about 5 wt. %, more preferably less than about 2 wt. %, still preferably less than about 1 wt. %, still preferably less than about 0.1%, most preferably less than about 0.01 wt. % of other crystal forms, e.g., amorphous or other crystal forms. For example, the Salt Crystals of the Present Invention is in Form A and are free or substantially free of other salt forms, e.g., greater than 90 wt. % of Form A with less than 10 wt. % of the amorphous or other crystal forms. In another example, the Salt Crystals of the Present Invention is in Form B free or substantially free of other salt forms, e.g., greater than 90 wt. % of Form B with less than 10 wt. % of the amorphous or other crystal forms. Preferably, the Salt Crystals of the Present Invention comprises greater than 99 wt. % a single crystal form.

The term “patient” includes human or non-human.

The term “solvate” refers to crystalline solid adducts containing either stoichiometric or nonstoichiometric amounts of a solvent incorporated within the crystal structure. Therefore, the term “non-solvate” form herein refers to salt crystals that are free or substantially free of solvent molecules within the crystal structures of the invention. Similarly, the term “non-hydrate” form herein refers to salt crystals that are free or substantially free of water molecules within the crystal structures of the invention.

The term “amorphous” form refers to solids of disordered arrangements of molecules and do not possess a distinguishable crystal lattice.

The crystallinity or the morphology of the Salt Crystals of the Present Invention may be determined by a number of methods, including, but not limited to single crystal X-ray diffraction, X-ray powder diffraction, polarizing optical microscopy, thermal microscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA), infrared adsorption spectroscopy and Raman spectroscopy. Characterization of solvates or hydrates or lack thereof may also be determined by DSC and/or TGA.

The Solid Salt of the Present Invention may be obtained by methods generally known in the art and provided in U.S. Pat. No. WO 2000/77010; WO 2000/77002; WO 200077001; U.S. Pat. Nos. 6,713,471; 6,552,017; 7,081,455, 7,071,186; reissued U.S. Pat. Nos. 39,680; 39,679, e.g., reacting the free base with the toluenesulfonic acid monohydrate in a solvent, e.g., methanol, ethanol, isopropol, ethyl acetate, methylene chloride, toluene, tetrahydrofuran, acetone, acetonitrile, water or the like.

Crystallization methods are also well known in the art. Crystallization of the Salt of the Present Invention may be performed by either reacting the Free Base of the Present Invention with the toluenesulfonic acid, e.g., toluenesulfonic acid monohydrate in a solvent, e.g., C_1-4alcohol (e.g., methanol, ethanol, isopropyl alcohol), acetone, ethyl acetate, n-propyl acetate, acetonitrile and tetrahydrofuran and optionally cooling said solution down, e.g., to 0°-25° C.

Alternative to starting with the free base, crystallization of the Salts of the present invention may be carried out by first dissolving the salt, e.g., the Salts or Salt Crystals of the Current Invention, e.g., any of formulae 1.1-1.29, in a single solvent, e.g., C_1-4alcohol (e.g., methanol, ethanol, isopropyl alcohol), acetone, ethyl acetate, n-propyl acetate, acetonitrile and tetrahydrofuran, preferably, optionally at an elevated temperature, e.g., greater than 25° C., e.g., at 30°-75° C., preferably in a minimum amount of solvent (i.e., saturate the solution). Crystallization may then be induced by a number of ways, e.g., in a single solvent system by (a) allowing the solvent to evaporate slowly until crystals are formed; (b) slowing down the rate of stirring or stopping agitation completely; (c) cooling the solution down, e.g., to less than 25° C., e.g., to −10°-20° C.; (d) adding crystal seeds, e.g., preferably, but not necessarily, the crystal of the compound which is being crystallized; or any combinations thereof; or in a multi-solvent system by adding an antisolvent(s), preferably a solvent having different polarity from the dissolution or the main solvent, e.g., water, heptane, hexane, butanone, or toluene or mixtures thereof to a solution of the compound in a methanol, ethanol or tetrahydrofuran solvent system.

In a particular embodiment, the Salt Crystals Form A of the Present Invention may be prepared by reacting 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone free base with a stoichiometric amount of p-toluenesulfonic acid monohydrate in about 2-5 mL/g, preferably 3.5 mL/g of isopropanol per gram of the Free Base of the Present Invention and optionally cooling said solution until crystals start to form, e.g., to 15-25° C. Optionally, the solution may be seeded with the Salt Crystals of the Present Invention (if available).

In another embodiment of the invention, Salt Crystals Form B may be prepared by reacting 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone free base in ethanol, e.g., 2-5 mL/g, preferably 3 mL/g of ethanol per gram of the free base with a stoichiometric amount of p-toluenesulfonic acid monohydrate. Optionally, another 0.5-1 mL of ethanol per gram of free base may be added and the mixture is cooled, e.g., to less than 25° C., e.g., about 10° C. until crystals are formed.

EXAMPLE 1

Preparation of the Salt Crystals Form A

Dissolve the stating material, 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone (free base) (178.4 g, 0.453 mol, 1 eq) in 2-Propanol (624.4 mL, 3.5 mL mLtg). Add charcoal (10 g) and stir the resulting mixture for 10-20 minutes at room temperature. After this time, remove charcoal by filtration. Wash the filter cake with 2-Propanol (89.2 mL, 0.5 mL/g SM). Transfer the combined filtrate to a 3 L 3-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, drying tube and thermocouple and placed in a cooling tub. Add the p-Toluenesulfonic acid monollydrate (86.24 g, 0.453 mol, 1 equivalent) in one portion (reaction exotherms to 33° C., clear dark brown is observed). Cool this solution to 15-25° C. using cold tap water. Seed the resulting solution or wait until solids start to form (usually takes 30-60 minutes). Thick beige/gray paste forms. Stir the resulting paste for a minimum of 3 hours at 15-25° C. Collect the solids by filtration (filtration and followed washes are quite slow). Wash the solids with 2-Propanol (2×150 mL, room temperature), and then with heptane (room temperature, 2×150 mL). Dry the solids in a vacuum oven at 35° C. to a constant weight. Yield: 214 g, 0.378 mol, 83.4%. HPLC=93.2% purity. Chiral HPLC=de 100%. Melting Point 179°-181° C. The following characterization is performed:

Infrared Spectroscopy:

Two to six milligrams of sample are ground with ca. 200 mg of KBr. The KBr pellet spectrum is obtained on a small sample of this mixture pressed into a suitable pellet using a Wilk's mini-press. The spectrum is defined by 16 scans at 2 cm₋₁ resolution. The spectrum is disclosed in FIG. 1. Infrared spectra for Salt Crystal Form A (FIG. 1 and FIG. 2) are consistent with the tosylate Salt structure. Selected infrared bands and their attributes are listed

in Table 1.

TABLE 1

Tentative Fourier Transform Infrared Spectrometry Band Assignments
for Salt Crystals Form A
BAND TENTATIVE ASSIGNMENT

2952 C—H3, wag
2824 C—H, stretch
2581 C—N, stretch
1687 C═O, stretch
1617 C═C, aromatic, bend
1599 C═C, aromatic bend
1506 C═C, aromatic, stretch
1328 S═O, bend
1231 S═O, bend
1162 C—N, stretch
1010 S═O, stretch
817  C—H, aromatic stretch
681  C—H, bend
569  C—F, stretch

Mass Spectrometry

Positive ion electrospray high-resolution mass spectrometry is carried out on Salt Crystals Form A (dissolved in 1:1 Acetonitrile: Water) with a PE Sciex Q-Star hybrid quadruple/time of flight mass spectrometer. The mass spectrometer is internally calibrated using poly (ethylene gycol) monomethyl ether 350 (PPGMME 350). Two PEGMME 350 signals at m/z 363.1995 and 451.2519 are used to measure a (PEGMME350+Na)+ signal. This gave a value of 407.2261 which compares well with the calculated value of 407.2257. The sample signal is measured in a similar way and gives a value of m/z 394.2299, which is 1.0 ppm from the calculated value of 394.2295 for the protonated molecular ion of the free base. The interpretation of mass spectra (FIG. 3) Salt Crystals Form A conforms with the expected results based on the chemical structure.

NMR Spectroscopy

The 400 MGz ¹H (FIG. 4) and 100 MGz ¹³C (FIG. 5) NMR spectra for Salt Crystals Form A (Salt Crystals Form A, in DMSO-d6; TMS reference) are consistent with the structure of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluene sulfonic acid salt in all essential detail. Selected proton chemical shifts and coupling constants are listed in Table 2 and carbon chemical shifts are listed in Table 3.

The ¹H NMR spectrum (FIG. 4) shows signals due to 36 protons consistent with the proposed structure. The ¹³C NMR spectrum (FIG. 5) shows 28 signals consistent with the 27 unique carbons in the proposed structure. ¹H spectra assignments (in Table 2) and ¹³C spectral assignments for protonated carbons (in Table 3) are based on chemical shifts, COSY spectroscopy, HMQC spectroscopy and DEPT.

NMR spectra are recorded on a Varian 400 MHz Unity-plus NMR spectrometer equipped with a 5 mm ¹H/¹⁹F/¹⁵N-³¹P switchable probe. The ¹H spectrum is recorded using 60° rf pulses and 16 transients. The ¹³C NMR spectrum is recorded using WALTZ proton decoupling, 60° rf pulses and 4096 transients.

TABLE 2
Proton NMR Chemical Shifts for Salt Crystals Form A
##STR00002##
δ1H*	Mult†	J§	Int‡	Tentative Assignment**
9.22	br s		1	25
8.04	dd	8.8	2	1
7.52	d	8	2	23
7.36	t	9.0	2	2
7.12	dd	8.4, 0.8	2	22
6.60	t	7.6	1	12
6.51	d	7.2	1	11
6.42	d	7.6	1	13
3.58	dd	12	1	9
3.50-3.39	m		1, 1	16, 19
3.36-3.30	m		1, 1, 1	15, 10, 16
3.20	m		1	17
3.16-3.00	m	7.0	2, 2, 1	6, 8, 19
2.81	s		3	14
2.70	dt	10.1, 2.9	1	15
2.55	q	11.2	1	9
2.50				DMSO-d6
2.27	s		3	20
2.23	br s		1	18
2.11	m		1	18
2.01	m	7.6	2	7
*Chemical shift in ppm
**See structure for numbering
‡Signal integration in relative numbers of protons
†Multiplicity; s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, br = broad
§Proton-proton coupling in Hz

TABLE 3
Carbon NMR Chemical Shifts for Salt Crystals Form A
		Tentative
δ13C*	MULT†	Assignment‡
197.2	s	5
166.3 & 163.8	d	3
145.3, 137.9, 137.3,	s, s, s,	24, 21, 10a',
135.2, 133.1 & 133.1, 126.8	s, d, s	4, 13a, 10a
130.9 & 130.8	d	1
128.2	s	22
125.5	s	23
120.6	s	12
115.8 & 115.6	d	2
112.5	s	11
109.3	s	13
62.2	s	17
55.6	s	8
52.5	s	9
49.8	s	16
47.7	s	19
43.7	s	15
39.5		DMSO-d6
38.5	s	10
37.0	s	14
34.9	s	6
21.6	s	18
20.8	s	20
18.0	s	7
*Chemical shift in ppm
‡See structure for numbering
†Multiplicity; s = singlet, d = doublet

Specific Rotation

The specific rotation is recorded on a Perkin Elmer model 343 Plus polarimeter operating at the sodium D-Line (589.3 nm) and utilizing a 5-s sample integration time. The sample temperature is maintained at 25° C. with a temperature controlled water-jacketed cell. The sample is prepared by dissolving ca. 475 mg of Salt Crystals Form A with MeOH in a 50-mL volumetric flask.

Ultraviolet-Visible Spectrophotometry

The ultraviolet/visible spectrum for Salt Crystals Form A can be found in FIG. 6. The spectra represent two different concentrations of Salt Crystals Form A in methanol. Two distinct maxima (227 nm 2 nm and 314 nm 2 nm) are found in the range of 200 nm to 500 nm. The molar extinction coefficient at 227 nm is calculated to be 43513 L*mol-1*cm-1. The molar extinction coefficient at 314 nm is calculated to be 4246 L*mol-1*cm-1. Calculation of Extinction Coefficient based on Salt Crystals Form A with a MW of 565.7. The spectra are recorded on a Cary 3 UV/Visible spectrophotometer using a 1.0 cm quartz cell. The samples are prepared in duplicate for each maxima wavelength at concentrations of ca. 0.12 mg/mL, 0.06 mg/mL for the maxima at 314 nm and ca. 0.012 mg/mL and 0.006 mg/mL for the maxima at 227 nm to optimize the spectra at each maxima examined. All samples are dissolved in methanol.

Residue on Ignition

Residue on ignition is performed according to USP 29/NF 24 (Supplement 2) 2006, General Chapter <281>. A sample of ca. 1 g is accurately weighed directly into a platinum crucible that has been previously ignited, cooled and weighed. The crucible is heated until the sample is thoroughly charred, then cooled. The residue is then moistened with approximately 1 mL of concentrated sulfuric acid, heated gently until white fumes no longer evolved, then ignited in a muffle furnace at 600±50° C. until all the carbon within the crucible was consumed. The sample is then cooled to room temperature in a desiccator. After cooling, the weight of residue is taken. The moistening with sulfuric acid, heating and igniting as before, using a 30 minute ignition period, is repeated, until two consecutive weighings of the residue does not differ by more than 0.5 mg. Results: Residue on Ignition=0.05%.

Elemental Analysis

The elemental analysis of sample Salt Crystals Form A is found to be consistent with the empirical formula. Samples are analyzed in duplicate and oxygen is determined by difference.

	Element
		Hydro-	Nitro-
	Carbon	gen	gen	Oxygen3	Fluorine	Sulfur
Percent	65.48	6.63	7.44	11.15	3.39	5.92
Experimental
Value1
Percent	65.82	6.41	7.43	11.31	3.36	5.67
Theoretical
Value2
Percent	−0.34	0.22	0.01	−0.16	0.03	0.25
Difference
1Average (n = 2)
2ChemWindow V.5.1
3Oxygen determined by difference (Halogens interfere with the direct measurement of Oxygen)

X-Ray Powder Diffraction (XRPD)

The XRPD pattern of Salt Crystals Form A is shown in FIG. 7 along with some of the more prominent 2θ values. Table 4 shows a listing of the more prominent 2θ angles, d-spacings and relative intensities.

XRPD data is collected at ambient temperature on a PANalytical X'Pert θ/θ diffractometer, operating with copper radiation at 45 kV and 40 mA, using an X'Celerator detector. Unmilled sample is placed on a flat stainless steel sample holder and leveled using a glass microscope slide. Incident beam optics consists of ⅛° fixed divergence slit, ¼° fixed anti-scatter slit, 0.04 rad Soller slit and nickel filter to filter out Kα2 radiation. Data is collected at 3° to 43° 2θ. A standard PC with Windows XP® operating system and PANalytical X'Pert Data Collector v 2.1a are used. X'Pert Data Viewer v 1.1a is used to plot the data. The unit is calibrated annually using NBS silicon powder as a standard.

TABLE 4
Salt Crystals Form A Some of the More Prominent 2θ Angles,
D-Spacing and Relative Intensities (Cu Kα Radation)
POSITION	HEIGHT	FWHM		RELATIVE
(°2θ)	(Cts)	(°2θ)	D-SPACING (Å)	INTENSITY (%)
5.6811	11807.77	0.1658	15.54391	100.00
8.6140	1582.45	0.1671	10.37709	13.40
11.3750	1379.81	0.1863	7.77273	11.89
12.1088	3074.71	0.2072	7.30333	26.04
13.3354	1329.25	0.1838	6.63416	11.26
15.7948	1845.19	0.2650	5.60626	15.63
16.0419	2633.59	0.1568	5.52046	22.30
16.4461	976.96	0.5368	5.38570	8.27
17.0309	7890.92	0.2151	5.20205	66.83
17.2606	1283.83	4.0000	5.13334	10.87
17.5531	1328.92	0.1966	5.04844	11.25
18.1581	2550.85	0.1871	4.88158	21.60
18.9968	2449.84	0.2219	4.66792	20.75
19.8889	3546.82	0.2456	4.46051	30.04
20.7510	559.67	0.0792	4.27711	4.74
21.6724	1855.28	0.1758	4.09730	15.71
22.5463	2825.63	0.2478	3.94041	23.93
23.4815	2226.62	0.1730	3.78556	18.86
23.7411	1604.25	0.1854	3.74475	13.59
24.3006	2777.58	0.1798	3.65978	23.52
25.9394	874.95	0.3670	3.43216	7.41
27.2321	673.90	0.2791	3.27209	5.71
28.3782	192.47	0.1700	3.14250	1.63
28.9055	158.09	0.1331	3.08636	1.34
29.6695	493.21	0.2567	3.00860	4.18
31.6106	374.66	0.1619	2.82814	3.17
32.2950	211.18	0.2236	2.76975	1.79
34.8530	401.29	0.6501	2.57211	3.40
37.5435	283.20	0.1845	2.39373	2.40
39.4972	264.36	0.2221	2.27971	2.24
40.2502	140.53	0.1475	2.23878	1.19
40.8303	125.14	0.1353	2.20830	1.06

XRPD patterns of FIG. 7B are collected using a PANalytical X'Pert Pro diffractometer. An incident beam of Cu Kα radiation is produced using an Optix long, fine-focus source. An elliptically graded multilayer mirror is used to focus the Cu Kα X-rays of the source through the specimen and onto the detector. Data are collected and analysed using X'Pert Pro Data Collector software (v.2.2b). Prior to the analysis, a silicon specimen (NIST SRM 640c) is analyzed to verify the Si 111 peak position. The specimen is sandwiched between 3 μm thick films, analyzed in transmission geometry, and rotated to optimize orientation statistics. A beam-stop is used to minimize the background generated by air scatting. Anti-scattering extension and He are not used. Soller slits are used for the incident and diffracted beam to minimize axial divergence. Diffraction patterns are collected using a scanning position-sensitive detector (X'Celerator) located 240 mm from the specimen. The data acquisition parameters for each pattern are displayed above the image in the Data section.

Differential Scanning Calorimetry (DSC)

The DSC scan for Salt Crystals Form A is shown in FIG. 8. The DSC scan shows a single endotherm with an onset temperature of 178.8° C., peak temperature of 180.8° C., and ΔH=63.6 J/g. DSC measurements are made using a Perkin Elmer Pyris 1 DSC system equipped with an intracooler 2P refrigeration unit. The Pyris 1 DSC is purged with nitrogen. Calibration is performed prior to analysis using an Indium standard at a 10° C./min heating rate. Approximately 1.7 mg of sample is weighed on a Sartorius microbalance in a tared Perkin Elmer 30 μL universal aluminum pan with holes in the lid, and sealed using a Perkin Elmer pan crimper press. The sample is heated from room temperature to 300° C. at 10° C./min.

Thermo Gravimetric Analysis (TGA)

The TGA scan for Salt Crystals Form A is shown in FIG. 8. The TGA analysis shows two regions of weight loss with a total weight loss of 0.46% through 200° C. TGA measurements are collected using a Perkin Elmer Pyris 1 TGA system purged with nitrogen. A 100-mg standard weight and Ni metal are used to verify balance and temperature calibrations, respectively. A sample of Salt Crystals Form A is heated from room temperature to 300° C. at 10° C./min.

Melting Point

A melting point determination is performed on an electro thermal capillary melting point apparatus. The sample is heated from a temperature of 160° C. at a ramp rate of 2° C./min. Capillary melting point data exhibit no true melting point as the material decomposes over the region of 176.8 through 181.0° C. Thus the endotherm does not represent melting.

EXAMPLE 2

Preparation of the Salt Crystals Form B

Equip a 500 mL 3-neck round bottom flask with a mechanical stirrer, nitrogen inlet, drying tube and thermocouple. Dissolve the starting material 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone in toluenesulfonic acid addition salt (7.62 g, 0.01936 mol, 1 equivalent) in Ethanol (200 proof (50 mL). Charge the solution of starting material in ethanol (step 2) to the flask. Add p-toluenesulfonic acid monohydrate (3.68 g, 0.01936 mol, 1 eq) in one portion followed by charcoal (3 g). Heat the resulting mixture to 75-80° C. and stir at this temperature for 5-10 minutes. After this time remove the charcoal by filtration and wash the filter cake with Ethanol (3×30 mL). Transfer the combined filtrate to a 1 L 3-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, drying the tube and thermocouple and placed in a cooling tub. Cool the solution to 0-5° C. Suspension forms during cooling. Dilute this suspension with heptane and stir at 0-5° C. for a minimum of 13 hours at this temperature. Collect the solids by filtration. Wash the solids with cold Ethanol (20 mL, 0-5° C.) and then with heptane (room temperature, 50 mL). Dry the solids in a vacuum oven at 35° C. to constant weight. Yield 7.2 g, 0.0127 mol, 65.7%. HPLC: 96.4%. Chiral HPLC: de 100%. Melting point 182-183° C.

EXAMPLE 3

Preparation of the Salt Crystals Form B

Dissolve the starting material, 66-H-113 Peak 1 (9.32 g, 0.02368 mol, 1 eq) in Ethanol (200 proof, 80 mL). Add charcoal (0.5 g) and stir the resulting mixture for 10-20 minutes at room temperature. After this time remove charcoal by filtration. Wash the filter cake with Ethanol (2×30 mL). Charge the solution of starting material in ethanol (from the previous step) to a 1 L 3-neck round bottom flask with a mechanical stiner, nitrogen inlet, drying tube and thermocouple the flask and placed in a cooling tub. Add p-Toluenesulfonic acid monohydrate (4.51 g, 0.02368 mol, 1 eq) in one portion at room temperature. Clear amber solution forms. Soon solids stat to form. Cool the resulting suspension to 0-5° C., stir for 1 hour at this temperature and then dilute with heptane (300 mL). Stir the suspension for a minimum of 13 hours at 0-5° C. After this time, obtain the solids by filtration (tan). Wash the solids cold with heptane (room temperature, 50 mL). Dry the solids in a vacuum oven at 35° C. to constant weight. Yield: 10.93 g, 0.01932 mol, 81.59%.

Salt Crystals of Form B has the following XRPD: The XRPD pattern of Salt Crystals Form B is shown in FIG. 9. Table 5 shows a listing of the more prominent 2θ angles, d-spacings and relative intensities.

TABLE 5
Pos.
[°2Th.]	Height [cts]	FWHM [°2Th.]	d-spacing [Å]	Rel. Int. [%]
4.1373	3800.46	0.1299	21.35763	83.44
5.6541	3600.03	0.1299	15.63088	79.04
8.2430	526.80	0.3897	10.72658	11.57
10.3839	1089.03	0.1299	8.51937	23.91
11.3760	389.27	0.1624	7.77853	8.55
12.1103	1193.49	0.1948	7.30844	26.20
13.3099	544.61	0.1624	6.65232	11.96
14.1235	732.42	0.1299	6.27088	16.08
14.4743	583.24	0.1624	6.11969	12.81
14.8763	797.18	0.1299	5.95520	17.50
15.3532	1091.73	0.1624	5.77130	23.97
15.8535	1531.27	0.2922	5.59028	33.62
16.4465	1139.43	0.1948	5.39000	25.02
17.0544	4554.66	0.1948	5.19923	100.00
17.9466	668.96	0.3897	4.94274	14.69
18.1622	884.32	0.1299	4.88454	19.42
18.6277	693.40	0.1299	4.76350	15.22
18.9621	714.43	0.1624	4.68024	15.69
19.8255	884.11	0.2598	4.47833	19.41
20.3507	2433.40	0.1624	4.36392	53.43
20.6196	1910.18	0.2598	4.30762	41.94
21.6034	604.41	0.2598	4.11363	13.27
22.4973	1188.22	0.2598	3.95215	26.09
23.4609	494.32	1.0391	3.79196	10.85
24.3083	1191.59	0.1299	3.66167	26.16
25.1377	399.77	0.2598	3.54270	8.78
26.0351	473.87	0.2273	3.42260	10.40
27.2489	970.43	0.1624	3.27282	21.31
29.0199	91.17	0.6494	3.07701	2.00
31.5733	191.51	0.2598	2.83374	4.20
35.0279	94.76	1.0391	2.56178	2.08
37.6449	72.13	0.5196	2.38949	1.58
39.4614	89.16	0.5845	2.28359	1.96

EXAMPLE 4

Preparation of the Solid Salt or Salt Crystals of the Present Invention

Dissolve the starting material, 66-H-113 Peak 1 (5.28 g, 0.01342 mol, 1 eq) in Ethanol (200 proof, 35 mL). After this time, remove the charcoal by filtration. Wash the filter cake with 1 Ethanol (2×15 mL). Charge the solution of starting material in ethanol (from the previous step) to a 500 in L 3-neck round bottom flask equipped with a mechanical stirrer, nitrogen inlet, drying tube and thermocouple. The flask is placed in a cooling tub. Add p-Toluenesulfonic acid monohydrate (4.51 g, 0.02368 mol, 1 eq) in one portion at room temperature. Clear dark amber solution forms. Soon solids start to form. Cool the resulting suspension to 0-5° C. stir for 1 hour at this temperature and then dilute with heptane (200 mL). Stir the suspension for a minimum of 13 hours at 0-5′C. After this time remove the solids by filtration (tan). Wash the solids cold with heptane (room temperature, 40 mL). Dry the solids in a vacuum oven at 35° C. to constant weight. Yield: 5.95 g, 0.010617 mol, 78.37%

EXAMPLE 5

Preparation of the Solid Salt or Salt Crystals of the Present Invention

Crude free base is dissolved in EtOH (3000 mL), and is transferred to a 12 L, 3-necked, round-bottomed flask equipped with a mechanical stirrer, a N₂ inlet, and a temperature probe. To the stirred solution is then added 178.3 g of pTSA monohydrate (0.94 mol, 1 equiv relative to the crude free base). The batch is stirred at rt for ca. 1 h, and then the internal temperature is reduced to 2 to 4° C. with an ice bath. The batch is stirred at 2 to 4° C. for another 1 h, and the batch becomes a brownish white slurry. To the batch is then added heptane (6000 mL) through an addition funnel slowly in ca. 3 h. The resultant mixture is stirred at 2 to 4° C. for another 1 h, and is stored in a dark cold room for ca. 15 h. The batch is then filtered, and the solid is rinsed with heptane (1000 mL). After drying in a vacuum oven at 35 to 40° C. for 4 h, 345.8 g (61% yield) of a tan to brown solid was obtained. HPLC analysis showed the desired product at 96.9% purity. LC-MS analysis showed a major peak with M/e=394 (M+1). Chiral HPLC analysis showed the desired enantiomer (first eluting peak) with ca. 99.7% e.e. ¹H NMR (CDCl₃, 300 MHz) δ 2.12-2.32 (m, 4H), 2.35 (s, 3H), 2.52-2.70 (m, 2H), 2.80-2.94 (m, 1H), 2.90 (s, 3H), 3.02-3.24 (m, 5H), 3.26-3.42 (m, 4H), 3.50-3.76 (m, 4H), 6.48 (d, J=7.8 Hz, 1H), 6.55 (d, J=7.2 Hz, 1H), 6.74 (t, J=7.5 Hz, 1H), 7.04-7.14 (m, 2H), 7.18 (d, J=8.1 Hz, 2H), 7.78 (dd, J=6.3 Hz, J′=1.5 Hz, 2H), 7.92-7.98 (m, 2H), 10.60 (bs, 1H).

Claims

1. A 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′:4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt crystal form, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least two peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°±0.2° 2θ.

2. A pharmaceutical composition comprising the salt crystal form according to claim 1, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.

3. The salt crystal form according to claim 1, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.

4. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least three peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, ±0.2° 2θ, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.

5. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least four peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, ±0.2° 2θ, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.

6. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least five peaks selected from the group consisting of 5.68°, 12.11°, 16.04°, 17.03°, 18.16°, 19.00°, 21.67°, 22.55°, 23.48° and 24.30°, ±0.2° 2θ, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.

7. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least two peaks having D-spacing values selected from the group consisting of 15.543Å, 7.303Å, 5.520Å, 5.202Å, 4.882Å, 4.668Å, 4.097Å, 3.940Å, 3.786Å and 3.660Å, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.

8. The salt crystal form according to claim 1, wherein said salt crystal form exhibits an X-ray powder diffraction pattern comprising at least five peaks having D-spacing values selected from the group consisting of 15.543Å, 7.303Å, 5.520Å, 5.202Å, 4.882Å, 4.668Å, 4.097Å, 3.940Å, 3.786Å and 3.660Å, wherein the X-ray powder diffraction data is collected on a diffractometer operating with a copper anode with a nickel filter.

9. The salt crystal form according to claim 1, wherein said salt crystal form exhibits a differential scanning calorimetry pattern comprising a peak temperature range of 180° C. to 181° C.

10. A pharmaceutical composition comprising the salt crystal form according to claim 3, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.

11. A pharmaceutical composition comprising the salt crystal form according to claim 6, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.

12. A pharmaceutical composition comprising the salt crystal form according to claim 7, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.

13. A pharmaceutical composition comprising the salt crystal form according to claim 8, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.

14. A pharmaceutical composition comprising the salt crystal form according to claim 9, as active ingredient, together with a pharmaceutically acceptable diluent or carrier.

15. The pharmaceutical composition according to claim 10, wherein the composition comprises up to 10% by weight of other crystal forms of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt.

16. The pharmaceutical composition according to claim 10, wherein the composition comprises up to 10% by weight of amorphous forms of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt.

17. A 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt crystal form, wherein said salt crystal form is in triclinic, monoclinic, orthorhombic, tetragonal, rhombohedral, hexagonal or cubic crystal form.

18. The salt crystal form according to claim 17, wherein the salt crystal form exists as flakes or needles.

19. A method of manufacturing a pharmaceutical composition comprising 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt, wherein the method comprises the step of combining the salt crystal form according to claim 1 with at least one pharmaceutically acceptable diluent or carrier.

20. The method according to claim 19, wherein the 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt is the active ingredient of the pharmaceutical composition.

21. The method according to claim 19, wherein the 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt consists of 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone free base and toluenesulfonic acid in a 1:1 molar ratio.

22. A method of manufacturing a pharmaceutical composition comprising 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt, wherein the method comprises the step of combining the salt crystal form according to claim 3 with at least one pharmaceutically acceptable diluent or carrier.

23. A method of manufacturing a pharmaceutical composition comprising 4-((6bR,10aS)-3-methyl-2,3,6b,9,10,10a-hexahydro-1H-pyrido[3′,4′: 4,5]pyrrolo[1,2,3-de]quinoxalin-8(7H)-yl)-1-(4-fluorophenyl)-1-butanone toluenesulfonic acid addition salt, wherein the method comprises the step of combining the salt crystal form according to claim 6 with at least one pharmaceutically acceptable diluent or carrier.